Dataset Information

Early-life stress and amyloidosis in mice share pathogenic pathways involving synaptic mitochondria and lipid metabolism.

ABSTRACT:

Introduction

Early-life stress (ES) increases the risk for Alzheimer's disease (AD). We and others have shown that ES aggravates amyloid-beta (Aβ) pathology and promotes cognitive dysfunction in APP/PS1 mice, but underlying mechanisms remain unclear.

Methods

We studied how ES affects the hippocampal synaptic proteome in wild-type (WT) and APP/PS1 mice at early and late pathological stages, and validated hits using electron microscopy and immunofluorescence.

Results

The hippocampal synaptosomes of both ES-exposed WT and early-stage APP/PS1 mice showed a relative decrease in actin dynamics-related proteins and a relative increase in mitochondrial proteins. ES had minimal effects on older WT mice, while strongly affecting the synaptic proteome of advanced stage APP/PS1 mice, particularly the expression of astrocytic and mitochondrial proteins.

Discussion

Our data show that ES and amyloidosis share pathogenic pathways involving synaptic mitochondrial dysfunction and lipid metabolism, which may underlie the observed impact of ES on the trajectory of AD.

SUBMITTER: Kotah JM

PROVIDER: S-EPMC10984508 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Publications

Early-life stress and amyloidosis in mice share pathogenic pathways involving synaptic mitochondria and lipid metabolism.

Kotah Janssen M JM Kater Mandy S J MSJ Brosens Niek N Lesuis Sylvie L SL Tandari Roberta R Blok Thomas M TM Marchetto Luca L Yusaf Ella E Koopmans Frank T W FTW Smit August B AB Lucassen Paul J PJ Krugers Harm J HJ Verheijen Mark H G MHG Korosi Aniko A

Alzheimer's & dementia : the journal of the Alzheimer's Association 20231206 3

<h4>Introduction</h4>Early-life stress (ES) increases the risk for Alzheimer's disease (AD). We and others have shown that ES aggravates amyloid-beta (Aβ) pathology and promotes cognitive dysfunction in APP/PS1 mice, but underlying mechanisms remain unclear.<h4>Methods</h4>We studied how ES affects the hippocampal synaptic proteome in wild-type (WT) and APP/PS1 mice at early and late pathological stages, and validated hits using electron microscopy and immunofluorescence.<h4>Results</h4>The hipp ...[more]

PMID: 38055782

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Project description:Amyotrophic lateral sclerosis (ALS) is a poor-prognosis disease with puzzling pathogenesis and inconclusive treatments. We develop a mathematical model of ALS based on a system of interactive feedback loops, focusing on the mutant SOD1G93A mouse. Misfolded mutant SOD1 aggregates in motor neuron (MN) mitochondria and triggers a first loop characterized by oxidative phosphorylation impairment, AMP kinase over-activation, 6-phosphofructo-2-kinase (PFK3) rise, glucose metabolism shift from pentose phosphate pathway (PPP) to glycolysis, cell redox unbalance, and further worsening of mitochondrial dysfunction. Oxidative stress then triggers a second loop, involving the excitotoxic glutamatergic cascade, with cytosolic Ca2+ overload, increase of PFK3 expression, and further metabolic shift from PPP to glycolysis. Finally, cytosolic Ca2+ rise is also detrimental to mitochondria and oxidative phosphorylation, thus closing a third loop. These three loops are overlapped and positive (including an even number of inhibitory steps), hence they form a candidate multistationary (bistable) system. To describe the system dynamics, we model the interactions among the functional agents with differential equations. The system turns out to admit two stable equilibria: the healthy state, with high oxidative phosphorylation and preferential PPP, and the pathological state, with AMP kinase activation, PFK3 over expression, oxidative stress, excitotoxicity and MN degeneration. We demonstrate that the loop system is monotone: all functional agents consistently act toward the healthy or pathological condition, depending on low or high mutant SOD1 input. We also highlight that molecular interactions involving PFK3 are crucial, as their deletion disrupts the system's bistability leading to a single healthy equilibrium point. Hence, our mathematical model unveils that promising ALS management strategies should be targeted to mechanisms that keep low PFK3 expression and activity within MNs.

Dataset Information

Early-life stress and amyloidosis in mice share pathogenic pathways involving synaptic mitochondria and lipid metabolism.

Introduction

Methods

Results

Discussion

Publications

Early-life stress and amyloidosis in mice share pathogenic pathways involving synaptic mitochondria and lipid metabolism.

Similar Datasets

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